The present invention relates generally to 4,5-diaryl-3(2H)-furanone derivatives, methods of preparation therefor, and their use for the treatment of inflammation and inflammation-associated disorders as selective cyclooxygenase-2 inhibitors.
Prostaglandins are known to play an important roles in the inflammation. Since prostaglandins are produced from arachidonic acid by cyclooxygenases, inhibition of prostagalndin synthesis by cyclooxygenases, especially synthesis of PGE2, PGG2, and PGH2, leads to the treatment of inflammation.
There are at least two kinds of cyclooxygenases, cyclooxygenase-1 (abbreviated as COX-1) and cyclooxygenase-2 (abbreviated as COX-2). COX-1 is constitutively present in the gastrointestinal tract and the kidney, and is implicated to be responsible for the maintenance of the physiological homeostasis, such as gastrointestinal integrity and renal function. Interruption of COX-1 activity can lead to life-threatening toxicities to the gastrointestinal tract, such as ulceration and bleeding. In the meantime, COX-2 is induced upon inflammatory stimuli and known to be responsible for progression of inflammation. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders without incurring gastrointestinal toxicities.
Conventional non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, ketoprofen, ibuprofen, piroxicam, diclofenac etc, inhibit both COX-1 and COX-2, which would demonstrate their gastrointestinal toxicities as well as anti-inflammatory potency. However, they possess serious life-threatening gastrointestinal toxicities of bleeding and ulceration arising from their inhibition of COX-1, which limit their clinical use. Thus, a selective inhibitor of COX-2 can be useful as an anti-inflammatory therapeutic agent without the gastrointestinal toxicities, frequently occurring upon chronic use of conventional NSAIDs.
COX-2 inhibitors are implicated to possess a broad therapeutic spectrum besides anti-inflammatory, analgesic, and antipyretic activity. For example inhibition of COX-2 can prevent growth of certain types of cancer, especially colon cancer [J. Clin. Invest. 99, 2254 (1997)]. Another application of a COX-2 inhibitor can be found in the treatment of degenerative chronic neurological disorders, such as Alzheimer""s disease [Neurology 48, 626 (1997)]. COX-2 inhibition would be useful in reducing the infarct volume accompanying the stroke [J. Neuroscience 17, 2746 (1997)].
Recently two of COX-2 selective antiinflammatory drugs, celecoxib and rofecoxib, were introduced into the clinic for arthritic indications. Celecoxib and rofecoxib show anti-inflammatory potency comparable to conventional NSAIDs without COX-2 selectivity. In the meantime, these drugs show appreciably lower gastro-intestinal toxicities than conventional NSAIDs without COX-2 selectivity over COX-1. Thus, COX-2 selective inhibition itself can be enough for anti-arthritic potency and the inhibition of COX-1 is largely responsible for the gastrointestinal toxicities associated with conventional NSAIDs without COX-2 selectivity.
cis-1,2-Diaryl-alkenes or its structural-equivalents are known to be a pharmacophore for achieving selective COX-2 inhibition over COX-1 [Ann. Rep. Med. Chem. 32, 211 (1997)]. In case of celecoxib and rofecoxib, pyrazole and 2(5H)-furanone correspond to the scaffold, respectively. 
By adopting an appropriate scaffold for the cis-alkene pharmacophore, it would be possible to modulate both in vitro and in vivo characteristics of such inhibitors, such as dosing regimen, daily dose, clinical indications arising from tissue distribution characteristics, safety profile, and so on.
In this invention, 3(2H)-furanone is adopted as a scaffold for COX-2 inhibitors. 3(2H)-furanone derivatives were prepared for use in the treatment of glaucoma [EP 0 737 476 A2]. However, there is no precedent case that 3(2H)-furanone derivatives have been ever used as COX-2 inhibitors. There is no reported case of 4,5-diaryl-3(2H)-furanone derivatives, either.
The 4,5-diaryl-3(2H)-furanone derivatives disclosed herein selectively inhibit COX-2 over COX-1 and relieve the effects of inflammation. 4,5-Diaryl-3(2H)-furanone derivatives of this invention do not show substantial inhibition of COX-1 and consequently show reduced gastrointestinal side effects. Thus, 4,5-diaryl-3(2H)-furanone derivatives of this invention are found useful as anti-inflammatory agents with significantly reduced gastrointestinal side effects, when compared with conventional NSAIDs.
The present invention provides a novel class of potent selective COX-2 inhibitors.
The present invention provides a novel class of 3(2H)-furanone derivatives as selective COX-2 inhibitors, which are represented by Formula I: 
or a pharmaceutically-acceptable salt thereof, wherein:
X represents halo, hydrido, or alkyl;
Y represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio;
Z represents oxygen or sulfur atom;
R1 and R2 are selected independently from lower alkyl radicals, or form a 4- to 6-membered aliphatic or hetero cyclic group, taken together with the 2-position carbon atom of the 3(2H)-furanone ring;
and AR represents a substituted or non-substituted aromatic group of 5 to 10 atoms.
The present invention further provides methods for preparing 3(2H)-furanone derivatives of Formula I.